Comparison between two-dimensional and three-dimensional quantitative coronary angiography for the prediction of functional severity in true bifurcation lesions: Insights from the randomized DK-CRUSH II, III, and IV trials.

OBJECTIVE: This study investigated the diagnostic accuracy of three-dimensional quantitative coronary angiography (3D-QCA) compared with conventional 2D-QCA for predicting functional severity assessed by fractional flow reserve (FFR) for true bifurcation lesions. METHODS: Based on pooled data from the randomized DK-CRUSH II, III, and IV trials, we evaluated the patients with true bifurcation lesions who underwent coronary angiography together with functional evaluations using FFR in both the main vessel and the side branch. Off-line 2D- and 3D-QCA analyses were conducted using dedicated bifurcation QCA analysis software. Measurements of minimum lumen diameter (MLD), percentage diameter stenosis (% DS), and minimum lumen area (MLA) were compared between 2D- and 3D-QCA, and we evaluated their predictive values of functionally significant FFR. RESULTS: Ninety patients were eligible for enrollment in the present study. In the main vessel, MLA measured by 3D-QCA was the most accurate predictor of FFR <0.75 (C statistic 0.85, P < 0.001), while MLD measured by 2D-QCA was a similarly accurate predictor (C statistic 0.85, P < 0.001). In the side branch, the best metrics for predicting FFR <0.75 were % DS measured by 2D-QCA with a C statistic value of 0.91 (P < 0.001) and MLA measured by 3D-QCA with a C statistic value of 0.81 (P < 0.001). However, both 2D- and 3D-QCA metrics exhibited low accuracies for predicting FFR <0.75 in intermediate bifurcation lesions. CONCLUSIONS: 3D-QCA analysis for true bifurcation lesions did not improve the predictive accuracy of functionally significant FFR compared with 2D-QCA analysis. In lesions with intermediate stenosis, the diagnostic performance of both 2D- and 3D-QCA-derived measurements in differentiating functional severity is limited.

Comparison of intravascular ultrasound guided versus angiography guided drug eluting stent implantation: a systematic review and meta-analysis.

BACKGROUND: Intravascular ultrasound (IVUS) can be a useful tool during drug-eluting stents (DES) implantation as it allows accurate assessment of lesion severity and optimal treatment planning. However, numerous reports have shown that IVUS guided percutaneous coronary intervention is not associated with improved clinical outcomes, especially in non-complex patients and lesions. METHODS: We searched the literature in Medline, the Cochrane Library, and other internet sources to identify studies that compare clinical outcomes between IVUS-guided and angiography-guided DES implantation. Random-effects model was used to assess treatment effect. RESULTS: Twenty eligible studies with a total of 29,068 patients were included in this meta-analysis. The use of IVUS was associated with significant reductions in major adverse cardiovascular events (MACE, odds ratios [OR] 0.77, 95 % confidence intervals [CI] 0.71-0.83, P < 0.001), death (OR 0.62, 95 % CI 0.54-0.71, p < 0.001), and stent thrombosis (OR 0.59, 95 % CI: 0.47-0.73, P < 0.001). The benefit was also seen in the repeated analysis of matched and randomized studies. In stratified analysis, IVUS guidance appeared to be beneficial not only in patients with complex lesions or acute coronary syndromes (ACS) but also patients with mixed lesions or presentations (MACE: OR 0.69, 95 % CI: 0.60-0.79, p < 0.001, OR 0.81, 95 % CI 0.74-0.90, p < 0.001, respectively). By employing meta-regression analysis, the benefit of IVUS is significantly pronounced in patients with complex lesions or ACS with respect to death (p = 0.048). CONCLUSIONS: IVUS guidance was associated with improved clinical outcomes, especially in patients with complex lesions admitted with ACS. Large, randomized clinical trials are warranted to identify populations and lesion characteristics where IVUS guidance would be associated with better outcomes.

Sphingosine 1-phosphate receptor 2 promotes erythrocyte clearance by vascular smooth muscle cells in intraplaque hemorrhage through MFG-E8 production.

Intraplaque hemorrhage (IPH) accelerates atherosclerosis progression. To scavenge excessive red blood cells (RBCs), vascular smooth muscle cells (VSMCs) with great plasticity may function as phagocytes. Here, we investigated the erythrophagocytosis function of VSMCs and possible regulations involved. Based on transcriptional microarray analysis, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that genes up-regulated in human carotid atheroma with IPH were enriched in functions of phagocytic activities, while those down-regulated were enriched in VSMCs contraction function. Transcriptional expression of Milk fat globule-epidermal growth factor 8 (MFG-E8) was also down-regulated in atheroma with IPH. In high-fat diet-fed apolipoprotein E-deficient mice, erythrocytes were present in cells expressing VSMC markers αSMA in the brachiocephalic artery, suggesting VSMCs play a role in erythrophagocytosis. Using immunofluorescence and flow cytometry, we also found that eryptotic RBCs were bound to and internalized by VSMCs in a phosphatidylserine/MFG-E8/integrin αVß3 dependent manner in vitro. Inhibiting S1PR2 signaling with specific inhibitor JTE-013 or siRNA decreased Mfge8 expression and impaired the erythrophagocytosis of VSMCs in vitro. Partial ligation was performed in the left common carotid artery (LCA) followed by intra-intimal injection of isolated erythrocytes to observe their clearance in vivo. Interfering S1PR2 expression in VSMCs with Adeno-associated virus 9 inhibited MFG-E8 expression inside LCA plaques receiving RBCs injection and attenuated erythrocytes clearance. Erythrophagocytosis by VSMCs increased vascular endothelial growth factor-a secretion and promoted angiogenesis. The present study revealed that VSMCs act as phagocytes for RBC clearance through S1PR2 activation induced MFG-E8 release.

Rictor maintains endothelial integrity under shear stress.

Background: Endothelial injury induced by low shear stress (LSS) is an initiating factor in the pathogenesis of various cardiovascular diseases, including atherosclerosis, hypertension, and thrombotic diseases. Low shear stress activates the mammalian target of rapamycin complex 2 (mTORC2) signaling pathway. Rictor, the main constituent protein of mTORC2, is involved in vascular development. However, the impact of conditional Rictor ablation on endothelial homeostasis, especially on endothelial-specific markers, such as vascular endothelial-cadherin (VE-cadherin) and von Willebrand factor (VWF), under blood flow stimulation is unclear. Objective: We aimed to investigate whether endothelial Rictor is involved in maintaining vascular endothelial integrity and the potential role of Rictor in atheroprone blood flow-mediated endothelial injury. Methods and results: Immunofluorescence staining showed that endothelial Rictor was successfully knocked out in a mouse model. Scanning electron microscopy (EM) detection revealed disruption of the endothelial monolayer in the thoracic aorta of Rictor-deficient mice. Furthermore, scanning electron microscopy and transmission electron microscopy showed that Rictor deletion disrupted endothelial integrity and expanded cell junctions in the left common carotid artery region. In vitro, low shear stress disrupted actin filament polarity and the promoted the translocation of vascular endothelial-cadherin, the key component of adherens junctions (AJs) in human umbilical vein endothelial cells. After Rictor downregulation by small interfering RNA, the translocation of vascular endothelial-cadherin and stress fibers increased. Rictor knockdown inhibited low shear stress-induced von Willebrand factor upregulation, and downregulation of vascular endothelial-cadherin decreased low shear stress-induced von Willebrand factor expression. These results suggest that vascular endothelial-cadherin/von Willebrand factor is a possible mechanism mediated by Rictor in the pathological process of low shear stress-induced endothelial injury. Conclusion: Rictor is a key protein that regulates endothelial integrity under vascular physiological homeostasis, and Rictor mediates low shear stress-induced endothelial injury by regulating adherens junctions and von Willebrand factor.

Low shear stress induces endothelial cell apoptosis and monocyte adhesion by upregulating PECAM­1 expression.

Low shear stress serves an important role in the initiation and progression of atherosclerotic lesions, with an impact on progression, but its detailed mechanisms are .not yet fully known. The present study aimed to investigate endothelial cell (EC) apoptosis, as well as monocyte adhesion induced by low shear stress and the potential underlying mechanisms. The expression of platelet endothelial cell adhesion molecule­1 (PECAM­1) was demonstrated to be enhanced in human umbilical vascular ECs with a trend that was associated with time when stimulated by low shear stress compared with unstimulated cells. EC apoptosis was increased under low shear stress compared with unstimulated cells, and knockdown of PECAM­1 inhibited this process. Furthermore, downregulation of PECAM­1 reduced monocyte adhesion induced by low shear stress compared with that in the negative control cells. Mechanistically, PECAM­1 small interfering RNA transfection increased Akt and forkhead box O1 phosphorylation under low shear stress conditions compared with that in the negative control cells. Collectively, the findings of the present study revealed that low shear stress induced EC apoptosis and monocyte adhesion by upregulating PECAM­1 expression, which suggested that PECAM­1 may be a potential therapeutic target for atherosclerosis.

Antithrombotic Strategies in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

The optimal strategy of antithrombotic therapy for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention remains to be a question to be answered. The major challenge in such population is the balance between the benefit of reduced stroke and coronary ischemic events, against the risk of increased bleeding complications. Thus, both thrombotic and bleeding risk assessments should be included into clinical decision-making process for such patients. Currently, there is limited evidence based on randomized trials with adequate power to show the superiority of any strategy in the beneficial profile of safety and efficacy, thus limited recommendations are provided by clinical guidelines. Given the recent advancement in this field, our review provided an overview of the available risk stratification schemes for stroke and bleeding risk for AF patients, discussed the multiple questions in the optimal regimens of oral antiplatelet and anticoagulation therapy, and summarized evidence and recommendations related to long-term antithrombotic therapy for AF patients receiving stent implications.

Downregulation of vascular endothelial growth factor receptor-2 under oxidative stress conditions is mediated by ß-transduction repeat-containing protein via glycogen synthase kinase-3ß signaling.

Vascular endothelial growth factor receptor-2 (VEGFR-2), which is a key determinant of the angiogenecic response, is decreased in diabetic mice under oxidative stress. ß-transduction repeat-containing protein (ß-TrCP) has been reported to participate in VEGFR-2 degradation in thyroid cancer cells. Additionally, glycogen synthase kinase-3ß (GSK­3ß) acts as a mediator in the ß-TrCP-induced degradation of several proteins. However, the role played by ß-TrCP and GSK­3ß in the degradation of VEGFR-2 in endothelial cells where hyperglycemia had been induced was not fully understood. In the present study, we aimed to analyze the mechanisms of VEGFR-2 degradation by studying excess reactive oxygen species (ROS) induced by hyperglycemia or glucose oxidase (GO). Human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of glucose (6.6, 19.8 and 33 mM), mannitol (33 mM) and GO (1 U/ml). Angiogenic function, ROS levels, the co-location of VEGFR-2 and ß-TrCP were evaluated. Cells were collected for RT-qPCR and western blot analysis. We noted that angiogenesis was impaired upon increasing the glucose concentration. When HUVECs were in a hyperglycemic state, ROS production increased, comparable to exposure to GO; GO catalyzes oxidation of glucose into H2O2 and D-glucono-δ-lactone. Phosphorylated VEGFR-2 was reduced by hyperglycemia while total VEGFR-2 was almost unaltered. However, VEGFR-2 was reduced when directly exposed to ROS, with resultant co-location of ß-TrCP and VEGFR-2. Through a co-immunoprecipitation assay, we noted that ubiquitinated VEGFR-2 was significantly augmented by excess ROS. Decreased VEGFR-2 caused by ROS was ameliorated by ß-TrCP siRNA, proteasome inhibitor MG132 and GSK­3ß activity inhibitor (lithium chloride and SB216763). We suggest that redundant ROS reduces VEGFR-2 through ß-TrCP-mediated VEGFR-2 degradation, which is postulated to be regulated by GSK-3ß.

Noninvasive fractional flow reserve derived from coronary computed tomography angiography for identification of ischemic lesions: a systematic review and meta-analysis.

Detection of coronary ischemic lesions by fractional flow reserve (FFR) has been established as the gold standard. In recent years, novel computer based methods have emerged and they can provide simulation of FFR using coronary artery images acquired from coronary computed tomography angiography (FFRCT). This meta-analysis aimed to evaluate diagnostic performance of FFRCT using FFR as the reference standard. Databases of PubMed, Cochrane Library, EMBASE, Medion and Web of Science were searched. Seven studies met the inclusion criteria, including 833 stable patients (1377 vessels or lesions) with suspected or known coronary artery disease (CAD). The patient-based analysis showed pooled estimates of sensitivity, specificity and diagnostic odds ratio (DOR) for detection of ischemic lesions were 0.89 [95%confidence interval (CI), 0.85-0.93], 0.76 (95%CI, 0.64-0.84) and 26.21 (95%CI, 13.14-52.28). At a per-vessel or per-lesion level, the pooled estimates were as follows: sensitivity 0.84 (95%CI, 0.80-0.87), specificity 0.76 (95%CI, 0.67-0.83) and DOR 16.87 (95%CI, 9.41-30.25). Area under summary receiver operating curves was 0.90 (95%CI, 0.87-0.92) and 0.86 (95%CI, 0.83-0.89) at the two analysis levels, respectively. In conclusion, FFRCT technology achieves a moderate diagnostic performance for noninvasive identification of ischemic lesions in stable patients with suspected or known CAD in comparison to invasive FFR measurement.

Clinical outcomes of "complete, partially complete, and incomplete" revascularisation at five-year follow-up after percutaneous intervention of unprotected left main coronary artery disease with drug-eluting stents.

AIMS: The study aimed to examine five-year clinical outcomes of complete (CR), partially complete (PCR), and incomplete revascularisation (ICR) in patients with unprotected left main coronary artery (ULMCA) disease treated with drug-eluting stents (DES). Completeness of revascularisation, defined as revascularisation of all vessels ≥1.5 or 2.5 mm in diameter, has been shown to correlate with outcomes after percutaneous coronary intervention (PCI). There are no data to compare revascularisation strategies on long-term clinical outcomes in patients undergoing PCI of ULMCA disease. METHODS AND RESULTS: This prospective registry enrolled 910 consecutive patients with ULMCA disease undergoing PCI with DES implantation. CR included patients who had a successful revascularisation of all diseased segments with diameter ≥1.5 mm. PCR included patients who had successful revascularisation of all diseased segments with diameter ≥2.5 mm. ICR included patients who did not achieve revascularisation for all diseased segments of diameter ≥2.5 mm. The primary endpoint was the incidence of major adverse cardiac events (MACE: a composite of cardiac death, myocardial infarction and repeat revascularisation) at five-year follow-up. CR was achieved in 386 (42.4%), PCR in 227 (25.0%), and ICR in 297 (32.6%) patients. Patients with ICR had a significantly higher rate of MACE (29.6% vs. 22.5% and 15.5%, p<0.001) and all-cause mortality (12.5% vs. 7.0% and 6.2%; p=0.006) than those with CR and PCR at five-year follow-up. After propensity score matching, patients with CR vs. PCR had similar incidences of MACE (hazard ratio [HR]: 1.16, 95% confidence interval [CI]: 0.78-1.74, p=0.46), mortality (HR: 1.27, 95% CI: 0.61-2.63, p=0.53), and cardiac death (1.8% vs. 4.5%; HR: 2.56, 95% CI: 0.80-8.17, p=0.11). On multivariable logistic regression analysis, ICR appears to be an outcome of poor clinical characteristics, comorbidities and complex coronary anatomy. CONCLUSIONS: In the treatment of patients with ULMCA disease, ICR was associated with worse long-term clinical outcomes than CR and PCR. PCR has clinical outcomes similar to CR in patients with ULMCA disease treated with DES.

Comparison of long-term in-stent vascular response between abluminal groove-filled biodegradable polymer sirolimus-eluting stent and durable polymer everolimus-eluting stent: 3-year OCT follow-up from the TARGET I trial.

The study sought to compare long-term optical coherence tomography (OCT)-based in-stent vascular response between the abluminal groove-filled biodegradable polymer sirolimus-eluting stent (SES) and the durable polymer everolimus-eluting stent (EES) in the TARGET I trial. The TARGET I trial was a prospective, multicenter, randomized clinical trial which enrolled 458 patients with single de novo lesions treated by abluminal groove-filled biodegradable polymer SES and EES. A subset of 43 patients underwent angiography and OCT examinations at 3 years. All OCT images were analyzed at 0.4 mm intervals. A similar increase in angiographic late lumen loss was observed in SES and EES (from 0.05 ± 0.05 vs. 0.05 ± 0.05 mm [p = 0.84] at 9 months to 0.25 ± 0.37 vs. 0.26 ± 0.19 mm [p = 0.99] at 3 years, respectively), without significant differences at 3 years in mean neointimal thickness of stent struts (SES: 0.13 ± 0.02 mm vs. EES: 0.13 ± 0.02 mm, p = 0.80); mean percentage of covered struts (SES: 99.2 % vs. EES: 99.3 %, p = 0.53), or malapposed strut rates (SES: 0.08 % vs. EES: 0.06 %, p = 0.15). The OCT-based in-stent vascular response evaluation found similar vascular healing for the two studied devices, indicating that the luminal loss in EES from 9 months to 3 years cannot be imputed on its coated biocompatible polymer.